The mTORC1-SLC4A7 axis stimulates bicarbonate import to enhance de novo nucleotide synthesis

• Published in: Molecular cell Vol. 82; no. 17; pp. 3284 - 3298.e7
• Main Authors: Ali, Eunus S., Lipońska, Anna, O’Hara, Brendan P., Amici, David R., Torno, Michael D., Gao, Peng, Asara, John M., Yap, Mee-Ngan F., Mendillo, Marc L., Ben-Sahra, Issam
• Format: Journal Article
• Language: English
• Published: 01.09.2022
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2022.06.008

Bicarbonate (HCO 3 − ) ions maintain pH homeostasis in eukaryotic cells and serve as a carbonyl donor to support cellular metabolism. However, whether the abundance of HCO 3 − is regulated or harnessed to promote cell growth is unknown. The mechanistic target of rapamycin complex 1 (mTORC1) adjusts cellular metabolism to support biomass production and cell growth. We find that mTORC1 stimulates the intracellular transport of HCO 3 − to promote nucleotide synthesis through the selective translational regulation of the sodium bicarbonate cotransporter SLC4A7. Downstream of mTORC1, SLC4A7 mRNA translation required the S6K-dependent phosphorylation of the translation factor eIF4B. In mTORC1-driven cells, loss of SLC4A7 resulted in reduced cell and tumor growth, and decreased flux through de novo purine and pyrimidine synthesis in human cells and tumors without altering the intracellular pH. Thus, mTORC1 signaling, through the control of SLC4A7 expression, harnesses environmental bicarbonate to promote anabolic metabolism, cell biomass, and growth. Ali et al. showed that bicarbonate (HCO 3 − ) is a limiting substrate for nucleotide synthesis in proliferating cells. In response to growth factors stimuli, the mTORC1-S6K-eIF4B axis promotes an increase in the sodium bicarbonate cotransporter SLC4A7 mRNA translation to harness environmental HCO 3 − for cellular nucleotide synthesis and growth.